Microplastics have become emerging contaminants, causing widespread concern about their potential toxic effects. In this study, the uptake and tissue accumulation of polystyrene microplastics (PS-MPs) in zebrafish were detected, and the toxic effects in liver were investigated. The results showed that after 7 days of exposure, 5 μm diameter MPs accumulated in fish gills, liver, and gut, while 20 μm diameter MPs accumulated only in fish gills and gut. Histopathological analysis showed that both 5 μm and 70 nm PS-MPs caused inflammation and lipid accumulation in fish liver. PS-MPs also induced significantly increased activities of superoxide dismutase and catalase, indicating that oxidative stress was induced after treatment with MPs. In addition, metabolomic analysis suggested that exposure to MPs induced alterations of metabolic profiles in fish liver and disturbed the lipid and energy metabolism. These findings provide new insights into the toxic effects of MPs on fish.